Autoimmune Encephalitis and Autoimmune Epilepsy

Author｜Shirley Rao

Layout Designer｜Cecilia Qin /Autoimmune Encephalitis/ Autoimmune encephalitis refers to a category of encephalitis mediated by autoimmune mechanisms. Clinically, it manifests as an acute or subacute onset, primarily characterized by deficits in recent memory, abnormal psychomotor behavior, and epileptic seizures. According to the 2014 International League Against Epilepsy (ILAE) practical definition of epilepsy, at this stage, acute provocation or acute symptomatic seizures cannot yet be definitively classified as epilepsy. Based on research findings and clinical practice, experts recommend defining the recovery and post-sequela periods of autoimmune encephalitis as follows: all cerebral symptoms, except for epileptic seizures, such as psychiatric disorders and extrapyramidal symptoms, should have disappeared. Post-encephalitic epilepsy typically results from brain structural damage caused by encephalitis, such as neuronal injury and gliosis, at which point the relevant antibodies no longer have an effect, resulting in negative antibody test results. However, the latent period for this progression remains uncertain and may range from several months to several decades. Therefore, Geis and colleagues recommend that epileptic seizures resembling those of autoimmune encephalitis during the acute phase should not be immediately diagnosed as epilepsy. They suggest conducting follow-ups for at least one year to observe whether non-provoked epileptic seizures persist, before deciding on the continuation of antiepileptic drug (AED) therapy.

/Autoimmune Epilepsy/ The concept of Autoimmune Epilepsy has evolved over the years. As far back as 1976, Ettlin and others suggested that epileptic discharges might result from an autoimmune response. In 1995, Barinaga proposed a link between autoimmune hyperactivity and epilepsy. Subsequent research confirmed the association between epilepsy and the immune system, leading to the concept of "immune-mediated epilepsy." In 2002, the International Autoimmunity Congress introduced the term "Autoimmune Epilepsy." Over time, as research advanced, the 2013 revision of the International League Against Epilepsy (ILAE) epilepsy classification defined autoimmune epilepsy as seizures resulting from evidence of autoimmune-mediated central nervous system inflammation. In 2017, a classification of six major etiologies for epilepsy was proposed, with immunological causes being a prominent research focus. The term "Autoimmune Epilepsy" gained widespread usage, yet it remained a subject of debate within the academic community. In July 2020, the ILAE Autoimmune and Inflammation Working Group introduced the term "Acute Symptomatic Seizures Secondary to Autoimmune Encephalitis and Autoimmune-Related Epilepsy." Both autoimmune encephalitis and autoimmune epilepsy are diagnoses at the etiological level. However, epidemiological studies suggest that the proportion of autoimmune epilepsy solely arising from autoimmune encephalitis is relatively low. In other words, the majority of autoimmune epilepsy patients do not have a preceding status of encephalitis, indicating that autoimmune epilepsy can exist independently of autoimmune encephalitis.

/Factors Predisposing Autoimmune Encephalitis to Progress into Autoimmune Epilepsy/

Antibodies

Currently, the longest known antibodies detected in the cerebrospinal fluid and blood of patients are anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, along with anti-gamma-aminobutyric acid B receptor (GABABR), anti-leucine-rich glioma-inactivated protein 1 (LGI1), and others. Most of these antibodies are surface membrane antibodies. 

Types of Viral Infections

Studies have revealed that various viral infections, such as herpes simplex virus, varicella-zoster virus, and influenza A virus, can trigger NMDAR encephalitis, which is the most common form of autoimmune encephalitis. The potential mechanisms by which viral infections induce autoimmune epilepsy include (1) Structural similarity between viral antigens and neuronal molecules triggering antibody production and subsequent immune responses; (2) Immune reactions leading to direct neuronal damage; (3) Different viral infections may induce the generation of distinct antibodies. 

Electroencephalography and Imaging Changes

Currently, abnormal findings on electroencephalograms (EEG) and neuroimaging studies are considered more valuable in predicting the development of autoimmune epilepsy after autoimmune encephalitis. Autoimmune epilepsy often displays characteristics of a "multifocal, multisource, dynamically evolving" pattern on EEG. Patients with fewer or absent interictal epileptic discharges on EEG are more likely to progress to chronic epilepsy. Various types of autoimmune encephalitis exhibit different functional imaging patterns. For instance, PET imaging in patients with anti-NMDAR encephalitis-associated epilepsy typically reveals a pattern of decreased metabolism, with high metabolism in the frontal and temporal lobes as well as the basal ganglia, and low metabolism in the parieto-occipital lobes. This metabolic pattern may change over time. On the other hand, anti-LGI1 encephalitis-associated epilepsy often shows high metabolism in the medial temporal lobes and bilateral basal ganglia in acute stages (before treatment) and normal or mildly increased metabolism in chronic or recovery stages (after treatment). 

Diagnostic and Therapeutic Precision

Early Immunotherapy in Combination with Antiepileptic Drugs (AEDs) is Crucial for Preventing and Improving the Prognosis of Autoimmune Encephalitis Accompanied by Epileptic Seizure Phenomena." 

/Conclusion and Perspectives/

Autoimmune encephalitis and autoimmune epilepsy are two diseases diagnosed based on etiology, and they share common features such as anti-neuronal antibodies and overlapping clinical presentations. Moreover, a minority of cases of autoimmune encephalitis may progress to autoimmune epilepsy. Therefore, prompt and careful differentiation between the two conditions and the subsequent selection of appropriate antiepileptic treatment is crucial for improving patient outcomes.